Therapeutic agents of neural protection and repair in multiple sclerosis (MS) require proof-of-concept studies in model human systems to evaluate evolving histopathologic processes. Development of anti-inflammatory agents for relapsing MS has been tremendously accelerated by the use of gadolinium-enhanced MRI to screen anti-inflammatory therapies in short clinical trials. Lack of a comparable screening method to promptly monitor the effect of potential neural reparative agents has impeded the development of such treatments. Diffusion basis spectrum imaging (DBSI) represents a novel data-driven modeling of diffusion weighted MRI signals to address the shortcomings of other quantitative imaging techniques. DBSI has successfully differentiated and quantified axon and myelin injury from cellular inflammation and edema, correlating with visual acuity in optic neuritis of experimental autoimmune encephalomyelitis (EAE) mice with post-MRI histological validation. Herein, we seek to apply the DBSI method to human optic nerve imaging to create a complete acquisition/analyses package available to multiple centers for collaborative trials. Based upon our prior investigations, we hypothesize that, (1) In patients who present with acute optic neuritis, longitudinal ON DBSI metrics of axon density and injury at baseline and change over 3 months will predict 6 month OCT-derived average retinal nerve fiber layer (RNFL) thickness, ganglion cell/inner plexiform layer (GCIP) thickness, and VEP amplitude. Longitudinal ON DBSI myelin integrity at baseline and change over 3 months will predict 6 month VEP latency. We also hypothesize that, (2): In subjects with past optic neuritis, DBSI-derived axon density and axonal injury will demonstrate a close relationship with RNFL (GCIP) thickness and VEP amplitude. DBSI-derived myelin integrity will demonstrate a close relationship with VEP latency. Contrast sensitivity will be best predicted by a model that incorporates both DBSI axon and myelin metrics. To address these hypotheses, the aims of this proposal includes: (1) Twelve previously healthy subjects presenting within 30 days onset of acute optic neuritis will undergo DBSI, VEP, and OCT at baseline, 3-, and 6- months; and (2) Forty subjects with MS and a past history of optic neuritis will undergo ON DBSI, OCT, VEP, and contrast sensitivity. Thirty age- and gender-matched controls will be collected at Washington University (WU) and Mt. Sinai School of Medicine (MSSM). At completion, we will have established the relationships of inflammation, axon injury, demyelination, and remyelination to visual outcomes in acute and remote optic neuritis as the first step for multi-center studies.